This invention relates to bridged nicotine analogs of N-octylnicotinium iodide (NONI) that have selective antagonist properties at xcex13xcex22-containing nicotinic receptor subtypes and to a method of using such compounds to treat central nervous system pathologies. The present invention also relates to pharmaceutical compositions containing these compounds, as well as various uses thereof.
Formula (I) below shows the structure of S-(xe2x88x92)-nicotine (NIC), which activates neuronal nicotinic receptors evoking release of dopamine (DA) from presynaptic terminals in the central nervous system (CNS). NIC is a legal substance of dependence that produces many of its effects on the CNS, some of which may be considered to be beneficial, e.g., mood elevation, arousal and learning and memory enhancement. NIC produces its effect by binding to a family of ligand-gated ion channels, stimulation by acetylcholine (ACh) or NIC causes the ion channel to open, and cations to flux with a resulting rapid (in msec) depolarization of the target cell.
Over the last 12 years, there has been a substantial increase in studies on brain nicotinic receptors. These nicotinic receptors are composed of four subunit domains: 2xcex1, xcex2, xcex3 and xcex4 or xcex5. Neuronal nicotinic receptors are composed of only two subunits, xcex1 and xcex2 and are believed to assemble with the general stoichiometry of 2xcex1 and 3xcex2. Eight subtypes of the xcex1 subunit (xcex12 to xcex19) and three subtypes of the xcex2 unit (xcex22 to xcex24) are found in CNS. The most common nicotinic receptor species in the brain is composed of two xcex14 and three xcex22 subunits, i.e., xcex14xcex22. These subunits display different, but overlapping, patterns of expression in the brain.
For the most part, the actual subunit compositions and stoichiometries of nicotinic receptors in the brain remain to be elucidated. Thus, neuronal nicotinic receptor subtype diversity originates from differences in the amino acid sequence at the subunit level and from the multiple combinations of assemblies of subunits into functional receptor proteins afford wide diversity of pharmacological specificity.
In spite of the extensive diversity in neuronal nicotinic receptor messenger RNA expression, only a limited number of tools are available to study the pharmacology of native receptors. Radioligands are used in many such studies. [3H]NIC appears to label the same sites in the brain as [3H]ACh. It has been estimated that over 90% of [3H]NIC binding in the brain is due to association with a receptor that is composed of xcex14 and xcex22 subunits. Also, nicotinic receptor subtypes can be studied using an assay such as NIC-evoked [3H]DA release from rat straital slices. Nicotinic receptors are located in the cell body and terminal areas of the nigrostriatal system. NIC facilitates DA release from striatal nerve terminals. Studies strongly suggest that the [3H]DA release assay is useful to probe the xcex13xcex22-containing subtype of the nicotinic receptor.
The structural and functional diversity of CNS nicotinic receptors has stimulated a great deal of interest in developing novel, subtype-selective agonists. Some of these agonists are currently being evaluated in clinical trials for cognitive enhancement and neuroprotective effects potentially beneficial for diseases such as Alzheimer""s and Parkinson""s Disease. Surprisingly, little attention a has been focused on developing subtype-selective antagonists for neuronal nicotinic receptors.
A class pyridino N-substituted nicotine analogs having formula (II) below are known antagonists that inhibit nicotine evoked [3H]DA release from dopaminergic nerve terminals in the brain. The abbreviated nomenclature is given in parentheses. 
These compounds are useful in the treatment of nicotine abuse, smoking cessation therapy, as an antidote for nicotine intoxication, treatment of cognitive disorders such as Alzheimer""s disease and for the treatment of Parkinson""s disease. The compounds and their method of use were the subject of U.S. Pat. No. 5,691,365, issued Nov. 25, 1997. The content of this patent is incorporated herein by reference.
The invention disclosed herein is directed to another new class of efficacious and subtype-selective nicotinic antagonists at nicotinic receptors in the CNS. These compounds comprise bridged nicotine analogs of NONI.
The present invention provides; for bridged nicotine analogs of N-octylnicotinium iodide (NONI) compounds having potent and selective antagonistic activity at neuronal nicotinic receptor subtypes. The compounds competitively inhibit CNS acting nicotinic receptor agonists that are acting as putative xcex13xcex22 neuronal nicotinic receptor in the CNS.
A preferred embodiment of the invention provides for a method of antagonizing the nicotinic receptor comprising administering of a pharmaceutically effective amount of a compound of the invention.
Still another embodiment the invention provides a method for the treatment of psychostimulant abuse (including nicotine abuse, amphetamine abuse, methamphetamine abuse, alcohol abuse and cocaine abuse), as smoking cessation therapy, as an antidote for nicotine intoxication comprising administering of a pharmaceutically effective amount of a compound according to the invention, as a therapeutic agent for the treatment of pathologies of the GI tract, including irritable bowel syndrome, colitis and related disorders.
This invention further provides a method of treatment of CNS disorders associated with the alteration of normal neurotransmitter release in the brain, including conditions such as Alzheimer""s disease as well as other types of dementia, Parkinson""s disease, cognitive dysfunction (including disorders of attention, focus and concentration), attention deficit syndrome, affective disorders, mood and emotional disorders such as depression, panic anxiety and psychosis, Tourette""s syndrome, schizophrenia, eating disorders and the control of pain comprising administering of a pharmaceutically effective amount of a compound according to the invention.
The above and other objects of the invention will become readily apparent to those of skill in the relevant art from the following detailed description and figures, wherein only the preferred embodiments of the invention are shown and described, simply by way of illustration of the best mode of carrying out the invention. As is readily recognized the invention is capable of modifications within the skill of the relevant art without departing from the spirit and scope of the invention.
The present invention provides, novel bridged-ring compounds corresponding to the schematic structure formulas III and IV below: 
wherein
A is a 1, 2 or 3 atom bridging species selected from straight chain or branched chain alkylene moiety having up to 3 atoms in the backbone thereof, or a substituted alkenylene moiety having up to 3 atoms in the backbone thereof, or a C(O), O, C(S), S, S(O) or S(O)2 containing alkylene moiety, provided however, that any heteroatom contained in A is separated from N by at least one carbon atom;
B is a 1, 2 or 3 atom bridging species selected from straight chain or branched chain alkylene moiety having up to 3 atoms in the backbone thereof, or a substituted alkenylene moiety having up to 3 atoms in the backbone thereof, or a C(O), O, N(Y1), C(S), S, S(O) or S(O)2 containing alkene moiety, wherein Y1 is hydrogen or lower alkyl or aryl;
R1 is selected from hydrogen, lower alkyl (e.g., C1-C10 alkyl, preferably C1-C6 alkyl, and more preferably methyl, ethyl, isopropyl or isobutyl) or an aromatic group-containing species;
R2 is selected from hydrogen or lower alkyl;
R3, R4 and R5 are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl; alkenyl; substituted alkenyl; alkynyl; substituted alkynyl; aryl; substituted aryl; alkylaryl; substituted alkylaryl; arylalkyl; substituted arylalkyl; arylalkenyl; substituted arylalkenyl; arylalkynyl; substituted arylalkynyl; heterocyclic; substituted heterocyclic; trifluoromethyl; halogen; cyano; nitro; S(O)Y2, S(O)2Y2, S(O)2OY2 or S(O)2NHY2, wherein each Y2 is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl, provided, however, that when R3, R4 or R5 is S(O)Y2, Y2 is not hydrogen, and further provided that when Y2 is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom; C(O)Y3, wherein Y3 is selected from hydrogen, alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality; OY4 or N(Y4)2 wherein each Y4 is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, that the OY4 or N(Y4)2 functionality is not conjugated with an alkenyl or alkynyl functionality; SY5 wherein Y5 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the SY5 functionality is not conjugated with an alkenyl or alkynyl functionality;
R6 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic or substituted heterocyclic; and
X is selected from chlorine, bromine, iodine, HSO4, 1/2SO2, CH3SO3, p-TsO or CF3SO3.
The junction between rings a and b can be either cis or trans geometry. The present invention includes all possible diastereomers and all enantiomeric forms as well as racemic mixtures. The compounds can be separated into substantially optically pure compounds. The compounds of the invention are nicotinic receptor antagonists. They inhibit NIC-evoked [3H]-DA release and inhibit [3H]-NIC binding.
It is preferred that A is either CH2 or CH2CH2; B is CH2, CH2CH2 or N(Y1) where Y1 is either hydrogen or methyl; R1 is a C1-C10 alkyl or more preferably a C1-C6 alkyl or even more preferably a C1-C4 alkyl such as a methyl, ethyl, isopropyl or isobutyl; R2 is hydrogen; R3, R4 and R5 are individually selected from the group consisting of hydrogen, halogen, alkyl and alkanoyl; R6 is a C4-C19 unbranched alkyl; and X is iodine.
As employed herein, the meaning of the aforementioned terms are defined as follows:
xe2x80x9clower alkylxe2x80x9d refers to straight or branched chain alkyl radicals having in the range of 1 up to 4 carbon atoms;
xe2x80x9calkylxe2x80x9d refers to straight or branched chain alkyl radicals having in the range of 1 up to 19 carbon atoms and xe2x80x9csubstituted alkylxe2x80x9d refers to alkyl radicals further bearing one or more substituents such as hydroxy, alkoxy (of a lower alkyl group), mercapto (of a lower alkyl group), aryl, heterocyclic, halogen, trifluoromethyl, cyano, nitro, amino, carboxyl, carbanate, sulfonyl, sulfonamide, and the like.
xe2x80x9ccycloalkylxe2x80x9d refers to cyclic ring-containing radicals containing in the range of 3 up to 8 carbon atoms and xe2x80x9csubstituted cycloalkylxe2x80x9d refers to cycloalkyl radicals further bearing one or more substituent as set forth above;
xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon double bond, and having in the range of 2 up to 19 carbon atoms and xe2x80x9csubstituted alkenylxe2x80x9d refers to alkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of 2 up to 19 carbon atoms and xe2x80x9csubstituted alkynylxe2x80x9d refers to alkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylxe2x80x9d refers to aromatic radicals having in the range of 6 up to 24 carbon atoms and xe2x80x9csubstituted arylxe2x80x9d refers to aryl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkylarylxe2x80x9d refers to alkyl-substituted aryl radicals and xe2x80x9csubstituted alkylarylxe2x80x9d refers to alkylaryl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylalkylxe2x80x9d refers to aryl-substituted alkyl radicals and xe2x80x9csubstituted arylalkylxe2x80x9d refers to arylalkyl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylalkenylxe2x80x9d refers to aryl-substituted alkenyl radicals and xe2x80x9csubstituted arylalkenylxe2x80x9d refers to arylalkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylalkynylxe2x80x9d refers to aryl-substituted alkynyl radicals and xe2x80x9csubstituted arylalkynylxe2x80x9d refers to arylalkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9caroylxe2x80x9d refers to aryl-substituted species such as benzoyl and xe2x80x9csubstituted aroylxe2x80x9d refers to aroyl radicals further bearing one or more substituents as set forth above; xe2x80x9cheterocyclicxe2x80x9d refers to cyclic radicals containing one or more heteroatoms as part of the ring structure, and having in the range of, 3 up to 24 carbon atoms and xe2x80x9csubstituted heterocyclicxe2x80x9d refers to heterocyclic radicals further bearing one or more substituents as set forth above; xe2x80x9cacylxe2x80x9d refers to alkyl-carbonyl species;
xe2x80x9chalogenxe2x80x9d refers to fluoride, chloride, bromide or iodide radicals; and
xe2x80x9can effective amountxe2x80x9d, when used in reference to compounds of the invention, refers to doses of compound sufficient to provide circulating concentrations high enough to impart a beneficial effect on the recipient thereof. Such levels typically fall in the range of about 0.001 up to about 100 mg/kg/day, with levels in the range of about 0.05 up to about 10 mg/kg/day being preferred.
The novel compounds of this invention are substantially optically pure.
The bridged nicotine analogs of NONI include compounds having formulas V and VI. The abbreviated nomenclature is given in parentheses. 
These compounds potently, competitively and selectively inhibit dopamine release induced by nicotine in superfused rat striatal slice preparations, while exhibiting weak insignificant inhibition of [3H]-nicotine and [3H]-MLA binding to rat striatal membranes. These compounds include, but are not limited to, the following specific compounds:
cis-1-methyl-8-octyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACO),
cis-1-methyl-8-nonyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACN),
cis-8-decyl-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACD),
cis-1-methyl-8-undecyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACU),
cis-8-dodecyl-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACDD).
cis-1-methyl-6-octyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-f]isoquinolin-6-ium iodide (BCO),
cis-1-methyl-6-nonyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-f]isoquinolin-6-ium iodide (BCN),
cis-6-decyl-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-f]isoquinolin-6-ium iodide (BCD),
cis-1-methyl-6-undecyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-f]isoquinolin-6-ium iodide (BCU), and
cis-6-dodecyl-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2,3-f]isoquinolin-6-ium iodide (BCDD).
These compounds can be prepared from corresponding free bases by reaction with an appropriate alkyl iodide using techniques known to those skilled in the art of organic synthesis. The requisite free bases can be synthesized using the techniques set forth by Chavdarian et al., J Org. Chem. 48:492 (1983), Glassco et al., J. Med. Chem. 36:3381 (1993) and Vernier et al., Bioorg. Med. Chem. Lett. 8:2173 (1998).
The invention will now be described in greater detail by reference to the following non-limiting examples.